tbuckley/cabot-search huggingface dataset:
Base-edited cynomolgus monkeys mimic core symptoms of STXBP1 encephalopathy
Authors: Zongyang Lu, Siting He, Jian Jiang, Ling Zhuang, Yan Wang, Guang Yang, Xiaoyu Jiang, Yanhong Nie, Jiqiang Fu, Xiaotong Zhang, Yong Lu, Xinyan Bian, Hung-Chun Chang, Zhiqi Xiong, Xingxu Huang, Zhen Liu, Qiang Sun
Journal: Molecular Therapy (2022)

(Molecular Therapy, 30, 2163–2175; June 2022) In the originally published version of this article, the authors made errors in the graphical abstract and Figure 1A. Both in the graphical abstract and Figure 1A, the substituted bases in plus and minus strand were incorrectly shown. Additionally, the citation to Figure 4A in the sentence “Scalp EEG recordings from A1 during 3–4 months postpartum showed a typical suppression-burst pattern in addition to interictal epileptiform discharges (Figures 4A)” has been corrected to “Figure 2A.” The citation to Figure 4D in the sentence “Only one C-to-T substitution (chr8: 43865425) observed in B2 was identified as a sgRNA-dependent off-target (Figure 4D)” has been corrected to “Figure 4F.” These errors have been corrected online. The authors regret these errors.Figure 1A3A-mediated C-to-T substitutions at the STXBP1 locus in nonhuman primates (original)View Large Image Figure ViewerDownload Hi-res image Download (PPT)Graphical abstract (corrected)View Large Image Figure ViewerDownload Hi-res image Download (PPT)Graphical abstract (original)View Large Image Figure ViewerDownload Hi-res image Download (PPT) Base-edited cynomolgus monkeys mimic core symptoms of STXBP1 encephalopathyLu et al.Molecular TherapyMarch 10, 2022In BriefIn this study, we generated cynomolgus monkeys carrying STXBP1 (R292H) mutation through base editing to mimic a clinical condition. The newborn STXBP1-edited monkeys exhibited focal epilepsy, especially typical EEG phenotypes. Biochemical analysis and single-cell sequencing showed dysregulation of proteins and cell type. Thus, our study reports a promising animal model for STXBP1-E. Full-Text PDF Open Access
Mannosylated poly(acrylic acid)-coated mesoporous silica nanoparticles for anticancer therapy
Authors: Haesoo Lee, Miseop Choi, Ha-Eun Kim, Minki Jin, Woo-Jin Jeon, Minwoo Jung, Hyelim Yoo, Jong-Hee Won, Young-Guk Na, Jae-Young Lee, Hasoo Seong, Hong-Ki Lee, Cheong-Weon Cho
Journal: Journal of Controlled Release (2022)
Differences in HADS and SF-36 scores 1 year after critical illness in COVID-19 patients
Authors: Roberta Teixeira Tallarico, Benjamin Deniau, Nicholas Fong, Jade Ghosn, Matthieu Legrand, Laurent Abel Amal Abrous, Claire Andrejak, François Angoulvant, Delphine Bachelet, Marie Bartoli, Sylvie Behilill, Marine Beluze, Krishna Bhavsar, Lila Bouadma, Minerva Cervantes-Gonzalez, Anissa Chair, Charlotte Charpentier, Léo Chenard, Catherine Chirouze, Sandrine Couffin-Cadiergues, Camille Couffignal, Marie-Pierre Debray, Dominique Deplanque, Diane Descamps, Alpha Diallo, Fernanda Dias Da Silva, Céline Dorival, Xavier Duval, Philippine Eloy, Vincent Enouf, Hélène Esperou, Marina Esposito-Farese, Manuel Etienne, Aline-Marie Florence, Alexandre Gaymard, Jade Ghosn, Tristan Gigante, Morgane Gilg, François Goehringer, Jérémie Guedj, Ikram Houas, Isabelle Hoffmann, Jean-Sébastien Hulot, Salma Jaafoura, Ouifiya Kafif, Antoine Khalil, Nadhem Lafhej, Cédric Laouénan, Samira Laribi, Minh Le, Quentin Le Hingrat, Soizic Le Mestre, Sophie Letrou, Yves Levy, Bruno Lina, Guillaume Lingas, Denis Malvy, France Mentré, Hugo Mouquet, Nadège Neant, Christelle Paul, Aurélie Papadopoulos, Christelle Paul, Ventzislava Petrov-Sanchez, Gilles Peytavin, Valentine Piquard, Olivier Picone, Manuel Rosa-Calatrava, Bénédicte Rossignol, Patrick Rossignol, Carine Roy, Marion Schneider, Richa Su, Coralie Tardivon, Jean-François Timsit, Sarah Tubiana, Sylvie Van Der Werf, Benoit Visseaux, Aurélie Wiedemann, N. Deye, C. Fauvaux, A. Mebazaa, C. Damoisel, D. Payen, E. Gayat, E. Azoulay, A. S. Moreau, L. Jacob, O. Marie, M. Legrand, M. Wolf, R. Sonneville, R. Bronchard, I. Rennuit, C. Paugam, J. P. Mira, A. Cariou, A. Tesnieres, N. Dufour, N. Anguel, L. Guerin, J. Duranteau, C. Ract, M. Leone, B. Pastene, T. Sharshar, A. Fayssoyl, J.-L. Baudel, B. Guidet, Q. Lu, WJie Gu, N. Brechot, A. Combes, S. Jaber, A. Pradel, Y. Coisel, M. Conseil, AVeillard Baron, L. Bodson, Jy Lefrant, L. Elotmani, A. Ayral, S. Lloret, S. Pily-Flouri, Jb Pretalli, Pf Laterre, V. Montiel, Mf Dujardin, C. Berghe
Journal: Intensive Care Medicine (2022)
Hinge disulfides in human IgG2 CD40 antibodies modulate receptor signaling by regulation of conformation and flexibility
Authors: Christian M. Orr, Hayden Fisher, Xiaojie Yu, Claude H.-T. Chan, Yunyun Gao, Patrick J. Duriez, Steven G. Booth, Isabel Elliott, Tatyana Inzhelevskaya, Ian Mockridge, Christine A. Penfold, Armin Wagner, Martin J. Glennie, Ann L. White, Jonathan W. Essex, Arwen R. Pearson, Mark S. Cragg, Ivo Tews
Journal: Science Immunology (2022)

Antibodies protect from infection, underpin successful vaccines and elicit therapeutic responses in otherwise untreatable cancers and autoimmune conditions. The human IgG2 isotype displays a unique capacity to undergo disulfide shuffling in the hinge region, leading to modulation of its ability to drive target receptor signaling (agonism) in a variety of important immune receptors, through hitherto unexplained molecular mechanisms. To address the underlying process and reveal how hinge disulfide orientation affects agonistic activity, we generated a series of cysteine to serine exchange variants in the hinge region of the clinically relevant monoclonal antibody ChiLob7/4, directed against the key immune receptor CD40. We report how agonistic activity varies with disulfide pattern and is afforded by the presence of a disulfide crossover between F(ab) arms in the agonistic forms, independently of epitope, as observed in the determined crystallographic structures. This structural "switch" affects directly on antibody conformation and flexibility. Small-angle x-ray scattering and ensemble modeling demonstrated that the least flexible variants adopt the fewest conformations and evoke the highest levels of receptor agonism. This covalent change may be amenable for broad implementation to modulate receptor signaling in an epitope-independent manner in future therapeutics.
Risk of Fractures and Subsequent Mortality in Alcohol-Related Cirrhosis: A Nationwide Population-Based Cohort Study
Authors: Axel Wester, Nelson Ndegwa, Hannes Hagström
Journal: Clinical Gastroenterology and Hepatology (2022)

Alcohol-related cirrhosis is linked to increased risk of fractures, but this has seldom been quantified nationally or compared against control subjects without cirrhosis. Here, we determined the rate and risk of fractures and postfracture mortality in patients with alcohol-related cirrhosis compared with individuals from the general population.In this nationwide population-based cohort study, data were retrieved from the Swedish National Patient Registry on 25,090 patients with alcohol-related cirrhosis from 1969-2016. Patients were matched for sex, age, and municipality with 239,458 control subjects from the Swedish Total Population Registry. Cox regression models were fitted to investigate the rates of fractures and postfracture mortality. The cumulative incidence of fractures was calculated while accounting for competing risks (death or liver transplantation).A total of 48,635 fractures occurred during 3,468,860 person-years of follow-up. Patients with alcohol-related cirrhosis had a higher fracture rate per 1000 person-years (38.7) than control subjects (13.3; adjusted hazard ratio, 3.8; 95% confidence interval, 3.6-3.9). The cumulative incidence of fractures was elevated for patients the first 19 years of follow-up, with a 5-year risk of 9.6% compared with 4.5% for control subjects. Patients with alcohol-related cirrhosis had a higher postfracture mortality rate compared with control subjects who also experienced a fracture, at both 30 days (adjusted hazard ratio, 1.6; 95% confidence interval, 1.4-1.8) and 1 year (adjusted hazard ratio, 1.8; 95% confidence interval, 1.7-2.0).Alcohol-related cirrhosis is associated with an almost 4-fold increased fracture rate, a higher risk of fractures the first 2 decades after initial diagnosis, and higher postfracture mortality. Preventive interventions to reduce modifiable fracture risk factors in this population are justified.
Longitudinal changes in sputum and blood inflammatory mediators during FeNO suppression testing
Authors: Simon Couillard, Rahul Shrimanker, Samuel Lemaire-Paquette, Gareth M Hynes, Catherine Borg, Clare Connolly, Samantha Jane Thulborn, Angela Moran, Sarah Poole, Sophie Morgan, Timothy Powell, Ian Pavord, Timothy Hinks
Journal: Thorax (2022)

To explore whether fractional exhaled nitric oxide (FeNO) non-suppression identifies corticosteroid resistance, we analysed inflammatory mediator changes during a FeNO suppression test with monitored high-intensity corticosteroid therapy. In linear mixed-effects models analysed over time, the 15 clinically distinct ‘suppressors’ (ie, ≥ 42% FeNO suppression) normalised Asthma Control Questionnaire scores (mean±SD, start to end of test: 2.8±1.4 to 1.4±0.9, p&lt;0.0001) and sputum eosinophil counts (median (IQR), start to end of test: 29% (6%–41%) to 1% (1%–5%), p=0.0003) while significantly decreasing sputum prostaglandin D 2 (254 (89–894) to 93 (49–209) pg/mL, p=0.004) and numerically decreasing other type-2 cytokine, chemokine and alarmin levels. In comparison, the 19 non-suppressors had persistent sputum eosinophilia (10% (1%–67%) despite high-intensity therapy) with raised end-test inflammatory mediator levels (1.9 (0.9–2.8)-fold greater than suppressors). FeNO non-suppression during monitored treatment implies biological corticosteroid resistance.
Transcriptomic Correlates of Tumor Cell PD-L1 Expression and Response to Nivolumab Monotherapy in Metastatic Clear Cell Renal Cell Carcinoma
Authors: Thomas Denize, Yue Hou, Jean-Christophe Pignon, Emily Walton, Destiny J. West, Gordon J. Freeman, David A. Braun, Catherine J. Wu, Saurabh Gupta, Robert J. Motzer, Michael B. Atkins, David McDermott, Toni K. Choueiri, Sachet A. Shukla, Sabina Signoretti
Journal: Clinical Cancer Research (2022)

Abstract Purpose: PD-L1 expression on tumor cells (TC) is associated with response to anti-PD-1-based therapies in some tumor types, but its significance in clear cell renal cell carcinoma (ccRCC) is uncertain. We leveraged tumor heterogeneity to identify molecular correlates of TC PD-L1 expression in ccRCC and assessed their role in predicting response to anti-PD-1 monotherapy. Experimental Design: RNA sequencing was performed on paired TC PD-L1 positive and negative areas isolated from eight ccRCC tumors and transcriptomic features associated with PD-L1 status were identified. A cohort of 232 patients with metastatic ccRCC from the randomized CheckMate-025 (CM-025) trial was used to confirm the findings and correlate transcriptomic profiles with clinical outcomes. Results: In both the paired samples and the CM-025 cohort, TC PD-L1 expression was associated with combined overexpression of immune- and cell proliferation–related pathways, upregulation of T-cell activation signatures, and increased tumor-infiltrating immune cells. In the CM-025 cohort, TC PD-L1 expression was not associated with clinical outcomes. A molecular RCC subtype characterized by combined overexpression of immune- and cell proliferation–related pathways (previously defined by unsupervised clustering of transcriptomic data) was enriched in TC PD-L1 positive tumors and displayed longer progression-free survival (HR, 0.32; 95% confidence interval, 0.13–0.83) and higher objective response rate (30% vs. 0%, P = 0.04) on nivolumab compared with everolimus. Conclusions: Both TC-extrinsic (immune-related) and TC-intrinsic (cell proliferation–related) mechanisms are likely intertwined in the regulation of TC PD-L1 expression in ccRCC. The quantitation of these transcriptional programs may better predict benefit from anti-PD-1-based therapy compared with TC PD-L1 expression alone in ccRCC.
Reply
Authors: Vladimir Loukachov, Karel van Dort, Robin Erken, Henk W. Reesink, Neeltje Kootstra
Journal: Hepatology (2022)

Dr. Abulaiti et al. pointed out that using an Alu‐RT‐PCR for the detection of transcription of integrated HBV limits the detection of chimeric transcripts. They show that only 15% of the chimeric transcripts obtained by RNA sequencing of liver samples from HBV‐related HCC patients contain an Alu sequence. Although we used a different patient population (chronic HBV patients without HCC), it is very likely that a proportion of chimeric transcripts lack an Alu sequence and are not detected by our Alu‐RT‐PCR.1 HBV integration occurs randomly across the whole genome.2 Alu sequences are also randomly distributed throughout the genome,3 and therefore we believe that quantification of chimeric HBV transcripts containing an Alu sequence may serve as a proxy of the transcriptional activity of integrated HBV. We agree with Abulaiti et al. that transcripts containing the ORF S and ORF X most likely arise from the same integrated HBV. In the total group of chronic HBV patients, we observed similar levels of S ORF and ORF X transcription (Figure 3).1 Our assay does not discriminate between integrants that either contain ORF S/X or ORF X alone, and transcriptional activity is expressed as ORF X transcripts corrected for the total amount of integrants containing X (Figure 4F). This may explain why no difference in ORF S and ORF X levels were observed. However, differences in transcriptional activity between patient subgroups (HBeAg‐negative CH, HBeAg‐positive CH, and HBeAg‐negative ChI) were observed for ORF S and ORF X (Figure 4C,F), which could be explained by differences in the epigenetic modification of integrated HBV between the different stages of disease.4
Motor learning selectively strengthens cortical and striatal synapses of motor engram neurons
Authors: Fuu-Jiun Hwang, Richard H. Roth, Yu-Wei Wu, Yue Sun, Destany K. Kwon, Yu Liu, Jun B. Ding
Journal: Neuron (2022)

Learning and consolidation of new motor skills require plasticity in the motor cortex and striatum, two key motor regions of the brain. However, how neurons undergo synaptic changes and become recruited during motor learning to form a memory engram remains unknown. Here, we train mice on a motor learning task and use a genetic approach to identify and manipulate behavior-relevant neurons selectively in the primary motor cortex (M1). We find that the degree of M1 engram neuron reactivation correlates with motor performance. We further demonstrate that learning-induced dendritic spine reorganization specifically occurs in these M1 engram neurons. In addition, we find that motor learning leads to an increase in the strength of M1 engram neuron outputs onto striatal spiny projection neurons (SPNs) and that these synapses form clusters along SPN dendrites. These results identify a highly specific synaptic plasticity during the formation of long-lasting motor memory traces in the corticostriatal circuit.
Dynamin is primed at endocytic sites for ultrafast endocytosis
Authors: Yuuta Imoto, Sumana Raychaudhuri, Ye Ma, Pascal Fenske, Eduardo Sandoval, Kie Itoh, Eva-Maria Blumrich, Hideaki T. Matsubayashi, Lauren Mamer, Fereshteh Zarebidaki, Berit Söhl-Kielczynski, Thorsten Trimbuch, Shraddha Nayak, Janet H. Iwasa, Jian Liu, Bin Wu, Taekjip Ha, Takanari Inoue, Erik M. Jorgensen, Michael A. Cousin, Christian Rosenmund, Shigeki Watanabe
Journal: Neuron (2022)

Dynamin mediates fission of vesicles from the plasma membrane during endocytosis. Typically, dynamin is recruited from the cytosol to endocytic sites, requiring seconds to tens of seconds. However, ultrafast endocytosis in neurons internalizes vesicles as quickly as 50 ms during synaptic vesicle recycling. Here, we demonstrate that Dynamin 1 is pre-recruited to endocytic sites for ultrafast endocytosis. Specifically, Dynamin 1xA, a splice variant of Dynamin 1, interacts with Syndapin 1 to form molecular condensates on the plasma membrane. Single-particle tracking of Dynamin 1xA molecules confirms the liquid-like property of condensates in vivo. When Dynamin 1xA is mutated to disrupt its interaction with Syndapin 1, the condensates do not form, and consequently, ultrafast endocytosis slows down by 100-fold. Mechanistically, Syndapin 1 acts as an adaptor by binding the plasma membrane and stores Dynamin 1xA at endocytic sites. This cache bypasses the recruitment step and accelerates endocytosis at synapses.
The monk parakeet (Myiopsitta monachus)
Authors: Zhen Huang, Luohao Xu
Journal: Trends in Genetics (2022)

Parrot genomes characteristically have a reduced chromosome number compared with other birds. Using high-quality chromosome-level assemblies of monk parakeet and several other parrot genomes, the evolutionary processes and patterns of chromosomal rearrangements among parrot lineages are depicted. A burst of one transposable element (CR1-psi) unique to parrots has been identified, which is thought to have directly or indirectly contributed to chromosomal rearrangements. Furthermore, the loss of two genes (ALC1 and PARP3), related to genome stability, serves as a likely explanation for the elevated rate of chromosomal rearrangements in parrots. The fusion of chromosomes 11 and 25 with ZW sex chromosomes has created a pair of neo-sex chromosomes. The chromosome number (2n = 48) of monk parakeets is the lowest among parrots, with only ten microchromosome pairs compared with ~30 pairs for a typical bird genome. The genome of monk parakeet is ~1.17 Gb in size, containing 24 pairs of chromosomes. The repeat content is ~14.6% and the GC content is 42.3%. In total, 17 294 protein-coding genes were annotated. Compared with other birds, at least 72 genes were lost in all parrots, including the monk parakeet. The size of the Z chromosome accounts for ~1/10 of the genome and it has experienced fusion with ancestral chromosome 11 and chromosome 25. The W chromosome has lost ~85% of the ancestral gene content but maintains a large size due to recent expansions of satellite DNA. The monk parakeet originates from South America but has become an invasive species in North America and Europe. In some regions, they are bred as bird pets. Many different breeds that vary in feather color have been established. Monk parakeet is the only parrot known to build a stick nest. Single nests can be integrated in a large compound nest. In the wild, they form large breeding colonies. The intelligence level of monk parakeets can reach that of a 3–5-year-old child. They have developed complex social and breeding behaviors. The average lifespan of monk parakeets is 25–30 years. This is very long considering the relatively small body size (~29 cm) of the monk parakeet. KINGDOM: Animalia PHYLUM: Chordata CLASS: Aves ORDER: Psittaciformes FAMILY: Psittacidae GENUS: Myiopsitta No interests are declared.
Reducing the environmental footprint of gastrointestinal endoscopy: European Society of Gastrointestinal Endoscopy (ESGE) and European Society of Gastroenterology and Endoscopy Nurses and Associates (ESGENA) Position Statement
Authors: Enrique Rodríguez de Santiago, Mario Dinis-Ribeiro, Heiko Pohl, Deepak Agrawal, Marianna Arvanitakis, Robin Baddeley, Elzbieta Bak, Pradeep Bhandari, Michael Bretthauer, Patricia Burga, Leigh Donnelly, Axel Eickhoff, Bu'Hussain Hayee, Michal F. Kaminski, Katarina Karlović, Vicente Lorenzo-Zúñiga, Maria Pellisé, Mathieu Pioche, Keith Siau, Peter D. Siersema, William Stableforth, Tony C. Tham, Konstantinos Triantafyllou, Alberto Tringali, Andrew Veitch, Andrei M. Voiosu, George J. Webster, Ariane Vienne, Ulrike Beilenhoff, Raf Bisschops, Cesare Hassan, Ian M. Gralnek, Helmut Messmann
Journal: Endoscopy (2022)

Abstract Climate change and the destruction of ecosystems by human activities are among the greatest challenges of the 21st century and require urgent action. Health care activities significantly contribute to the emission of greenhouse gases and waste production, with gastrointestinal (GI) endoscopy being one of the largest contributors. This Position Statement aims to raise awareness of the ecological footprint of GI endoscopy and provides guidance to reduce its environmental impact. The European Society of Gastrointestinal Endoscopy (ESGE) and the European Society of Gastroenterology and Endoscopy Nurses and Associates (ESGENA) outline suggestions and recommendations for health care providers, patients, governments, and industry. Main statements 1 GI endoscopy is a resource-intensive activity with a significant yet poorly assessed environmental impact. 2 ESGE-ESGENA recommend adopting immediate actions to reduce the environmental impact of GI endoscopy. 3 ESGE-ESGENA recommend adherence to guidelines and implementation of audit strategies on the appropriateness of GI endoscopy to avoid the environmental impact of unnecessary procedures. 4 ESGE-ESGENA recommend the embedding of reduce, reuse, and recycle programs in the GI endoscopy unit. 5 ESGE-ESGENA suggest that there is an urgent need to reassess and reduce the environmental and economic impact of single-use GI endoscopic devices. 6 ESGE-ESGENA suggest against routine use of single-use GI endoscopes. However, their use could be considered in highly selected patients on a case-by-case basis. 7 ESGE-ESGENA recommend inclusion of sustainability in the training curricula of GI endoscopy and as a quality domain. 8 ESGE-ESGENA recommend conducting high quality research to quantify and minimize the environmental impact of GI endoscopy. 9 ESGE-ESGENA recommend that GI endoscopy companies assess, disclose, and audit the environmental impact of their value chain. 10 ESGE-ESGENA recommend that GI endoscopy should become a net-zero greenhouse gas emissions practice by 2050.